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Challenges in translational drug research in neuropathic and inflammatory pain: the prerequisites for a new paradigm

Taneja, A; Della Pasqua, OE; Danhof, M; (2017) Challenges in translational drug research in neuropathic and inflammatory pain: the prerequisites for a new paradigm. European Journal of Clinical Pharmacology , 73 pp. 1219-1236. 10.1007/s00228-017-2301-8. Green open access

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Abstract

AIM: Despite an improved understanding of the molecular mechanisms of nociception, existing analgesic drugs remain limited in terms of efficacy in chronic conditions, such as neuropathic pain. Here we explore the underlying pathophysiological mechanisms of neuropathic and inflammatory pain, and discuss the prerequisites and opportunities to reduce attrition and high failure rate in the development of analgesic drugs. MEHTODS: A literature search was performed on preclinical and clinical publications aimed at the evaluation of analgesic compounds using MESH terms in PubMed. Publications were selected, which focused on 1) disease mechanisms leading to chronic/neuropathic pain and 2) drugable targets which are currently under evaluation in drug development. Attention was also given to biomarkers and pharmacokinetic-pharmacodynamic modelling. RESULTS: Multiple mechanisms act concurrently to produce pain, which is a non-specific manifestation of underlying nociceptive pathways. Whereas these manifestations can be divided into neuropathic and inflammatory pain, it is now clear that inflammatory mechanisms are a common trigger for both types of pain. This has implications for drug development, as the assessment of drug effects in experimental models of neuropathic and chronic pain is driven by overt behavioural measures. By contrast, the use of mechanistic biomarkers in inflammatory pain has provided the pharmacological basis for dose selection and evaluation of non-steroidal anti- inflammatory drugs (NSAIDs). CONCLUSION: A paradigm is required for the identification of relevant targets and candidate molecules whereby pain is coupled to the cause of sensorial signal processing dysfunction rather than to clinical symptoms. Biomarkers need to be identified that enable characterisation of drug binding and target activity, providing the basis for a more robust dose rationale in early clinical development. Such an approach may be facilitated by quantitative clinical pharmacology and evolving technologies in brain imaging, allowing accurate characterisation of target engagement, and prediction of treatment effects before embarking into large clinical trials.

Type: Article
Title: Challenges in translational drug research in neuropathic and inflammatory pain: the prerequisites for a new paradigm
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s00228-017-2301-8
Publisher version: http://dx.doi.org/10.1007/s00228-017-2301-8
Language: English
Additional information: Copyright© The Author(s) 2017 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: neuropathic pain, inflammatory pain, chronic pain, hyperalgesia, analgesics, PKPD modelling, drug development
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1561318
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